ABSTRACT: Osteoarthritic symptom is the key reason to seek medical assistance, yet there is no effective way to relieve osteoarthritis (OA)-induced pain. Our long term goal is to understand the discrepancy between the degree of cartilage degeneration and the actual experience of joint pain by investigating the neuroanatomical approaches in an experimental OA model followed by validation in human joint tissues. We propose that OA pain sensation can develop independently of progressive cartilage degeneration, and that severity of joint pain is due to cellular and molecular plasticity in the sensory neurons of the innervating dorsal root ganglion and pathological changes in synovium (e.g., synovitis, angiogenesis). We will identify the fundamental factors that facilitate pro- nociception in OA independently of the degree of cartilage degeneration. Our studies will also provide important empirical support for the development of clinical strategies to treat OA symptoms. Our results will provide a novel view of major disease-modified chronic pain mechanisms that accompany degeneration of knee joints in OA. At a broader level, results from this proposal will impact our conceptual perspectives and future research translation by clarifying relationships between musculoskeletal tissue degeneration and debilitating OA symptoms.